Structural and biochemical characterization of human adenylosuccinate lyase (ADSL) and the R303C ADSL deficiency-associated mutation.
Structural and biochemical characterization of human adenylosuccinate lyase (ADSL) and the R303C ADSL deficiency-associated mutation.
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DOI：
10.1021/bi300796y
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发表时间：
2012-08-21
期刊：
影响因子：
2.9
通讯作者：
Pegan SD
中科院分区：
文献类型：
--
作者：
Ray SP;Deaton MK;Capodagli GC;Calkins LA;Sawle L;Ghosh K;Patterson D;Pegan SD
Adenylosuccinate lyase (ADSL) deficiency is a rare autosomal recessive disorder, which causes a defect in purine metabolism resulting in neurological and physiological symptoms. ADSL executes two non-sequential steps in the de novo synthesis of AMP: the conversion of phosphoribosylsuccinyl-aminoimidazole carboxamide (SAICAR) to phosphoribosylaminoimidazole carboxamide (AICAR), which occurs in the de novo synthesis of IMP, and the conversion of adenylosuccinate (AMPS) to AMP, which occurs in the de novo synthesis of AMP and also in the purine nucleotide cycle, using the same active site. Mutation of ADSL’s arginine 303 to a cysteine is known to lead to ADSL deficiency. Interestingly, unlike other mutations leading to ADSL deficiency, the R303C mutation has been suggested to more significantly affect the enzyme’s ability to catalyze the conversion of SAMP than that of SAICAR to their respective products. To better understand the causation of disease due to the R303C mutation, as well as to gain insights as to why the R303C mutation potentially has a disproportional decrease in activity toward its substrates, the wild-type (WT) and the R303C mutation of ADSL were investigated enzymatically, and thermodynamically. Additionally, the X-ray structures of ADSL in its apo form as well as with the R303C mutation were elucidated, providing insight into ADSL’s cooperativity. By utilizing this information a model for the interaction between ADSL and SAICAR is proposed.
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影响因子：
5.2
作者：
Gitiaux, Cyril;Ceballos-Picot, Irene;Bahi-Buisson, Nadia
通讯作者：
Bahi-Buisson, Nadia
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
8
作者：
Sivendran, Sharmila;Colman, Roberta F.
通讯作者：
Colman, Roberta F.
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
3.5
作者：
Baresova, Veronika;Skopova, Vaclava;Kmoch, Stanislav
通讯作者：
Kmoch, Stanislav